tbuckley/cabot-search huggingface dataset:
Antibody and T cell responses to COVID-19 vaccination in patients receiving anticancer therapies
Authors: Sherin Juliet Rouhani, Jovian Yu, Daniel Olson, Yuanyuan Zha, Apameh Pezeshk, Alexandra Cabanov, Athalia R Pyzer, Jonathan Trujillo, Benjamin A Derman, Peter O'Donnell, Andrzej Jakubowiak, Hedy L Kindler, Christine Bestvina, Thomas F Gajewski
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Patients with cancer were excluded from phase 3 COVID-19 vaccine trials, and the immunogenicity and side effect profiles of these vaccines in this population is not well understood. Patients with cancer can be immunocompromised from chemotherapy, corticosteroids, or the cancer itself, which may affect cellular and/or humoral responses to vaccination. PD-1 is expressed on T effector cells, T follicular helper cells and B cells, leading us to hypothesize that anti-PD-1 immunotherapies may augment antibody or T cell generation after vaccination. Methods Antibodies to the SARS-CoV-2 receptor binding domain (RBD) and spike protein were assessed in patients with cancer (n=118) and healthy donors (HD, n=22) after 1, 2 or 3 mRNA vaccine doses. CD4 + and CD8 + T cell reactivity to wild-type (WT) or B.1.617.2 (delta) spike peptides was measured by intracellular cytokine staining. Results Oncology patients without prior COVID-19 infections receiving immunotherapy (n=36), chemotherapy (n=15), chemoimmunotherapy (n=6), endocrine or targeted therapies (n=6) and those not on active treatment (n=26) had similar RBD and Spike IgG antibody titers to HDs after two vaccinations. Contrary to our hypothesis, PD-1 blockade did not augment antibody titers or T cell responses. Patients receiving B-cell directed therapies (n=14) including anti-CD20 antibodies and multiple myeloma therapies had decreased antibody titers, and 9/14 of these patients were seronegative for RBD antibodies. No differences were observed in WT spike-reactive CD4 + and CD8 + T cell generation between treatment groups. 11/13 evaluable patients seronegative for RBD had a detectable WT spike-reactive CD4 + T cell response. T cells cross-reactive against the B.1.617.2 variant spike peptides were detected in 31/59 participants. Two patients with prior immune checkpoint inhibitor-related adrenal insufficiency had symptomatic hypoadrenalism after vaccination. Conclusions COVID-19 vaccinations are safe and immunogenic in patients with solid tumors, who developed similar antibody and T cell responses compared with HDs. Patients on B-cell directed therapies may fail to generate RBD antibodies after vaccination and should be considered for prophylactic antibody treatments. Many seronegative patients do develop a T cell response, which may have an anti-viral effect. Patients with pre-existing adrenal insufficiency may need to take stress dose steroids during vaccination to avoid adrenal crisis.
PRC2 Heterogeneity Drives Tumor Growth in Medulloblastoma
Authors: Jiaqing Yi, BongWoo Kim, Xuanming Shi, Xiaoming Zhan, Q. Richard Lu, Zhenyu Xuan, Jiang Wu
Journal: Cancer Research (2022)

Abstract Intratumor epigenetic heterogeneity is emerging as a key mechanism underlying tumor evolution and drug resistance. Epigenetic abnormalities frequently occur in medulloblastoma, the most common childhood malignant brain tumor. Medulloblastoma is classified into four subtypes including SHH medulloblastoma, which is characterized by elevated sonic hedgehog (SHH) signaling and a cerebellum granule neuron precursor (CGNP) cell-of-origin. Here, we report that the histone H3K27 methyltransferase polycomb repressor complex 2 (PRC2) is often heterogeneous within individual SHH medulloblastoma tumors. In mouse models, complete deletion of the PRC2 core subunit EED inhibited medulloblastoma growth, while a mosaic deletion of EED significantly enhanced tumor growth. EED is intrinsically required for CGNP maintenance by inhibiting both neural differentiation and cell death. Complete deletion of EED led to CGNP depletion and reduced occurrence of medulloblastoma. Surprisingly, medulloblastomas with mosaic EED levels grew faster than control wild-type tumors and expressed increased levels of oncogenes such as Igf2, which is directly repressed by PRC2 and has been demonstrated to be both necessary and sufficient for SHH medulloblastoma progression. Insulin-like growth factor 2 (IGF2) mediated the oncogenic effects of PRC2 heterogeneity in tumor growth. Assessing clones of a human medulloblastoma cell line with different EED levels confirmed that EEDlow cells can stimulate the growth of EEDhigh cells through paracrine IGF2 signaling. Thus, PRC2 heterogeneity plays an oncogenic role in medulloblastoma through both intrinsic growth competence and non–cell autonomous mechanisms in distinct tumor subclones. Significance: The identification of an oncogenic function of PRC2 heterogeneity in medulloblastoma provides insights into subclone competition and cooperation during heterogeneous tumor evolution.
Vitamins and Minerals to Prevent Cardiovascular Disease and Cancer
Authors: Jill Jin
Journal: JAMA (2022)

US Preventive Services Task Force; Carol M. Mangione, MD, MSPH; Michael J. Barry, MD; Wanda K. Nicholson, MD, MPH, MBA; Michael Cabana, MD, MA, MPH; David Chelmow, MD; Tumaini Rucker Coker, MD, MBA; Esa M. Davis, MD, MPH; Katrina E. Donahue, MD, MPH; Chyke A. Doubeni, MD, MPH; Carlos Roberto Jaén, MD, PhD, MS; Martha Kubik, PhD, RN; Li Li, MD, PhD, MPH; Gbenga Ogedegbe, MD, MPH; Lori Pbert, PhD; John M. Ruiz, PhD; James Stevermer, MD, MSPH; John B. Wong, MD
Effect of Intra-arrest Transport and Extracorporeal Cardiopulmonary Resuscitation on Functional Neurologic Outcome in Refractory Out-of-Hospital Cardiac Arrest
Authors: Yen-Po Lin, Yu-Syuan Chen
Journal: JAMA (2022)

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Optimizing the Time Course of Risks and Benefits of Acute Dual Antiplatelet Therapy for Stroke Prevention
Authors: Anthony S. Kim
Journal: JAMA Neurology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Vitamin, Mineral, and Multivitamin Supplementation to Prevent Cardiovascular Disease and Cancer
Authors: Carol M. Mangione, Michael J. Barry, Wanda K. Nicholson, Michael Cabana, David Chelmow, Tumaini Rucker Coker, Esa M. Davis, Katrina E. Donahue, Chyke A. Doubeni, Carlos Roberto Jaén, Martha Kubik, Li Li, Gbenga Ogedegbe, Lori Pbert, John M. Ruiz, James Stevermer, John B. Wong
Journal: JAMA (2022)

<h3>Importance</h3> According to National Health and Nutrition Examination Survey data, 52% of surveyed US adults reported using at least 1 dietary supplement in the prior 30 days and 31% reported using a multivitamin-mineral supplement. The most commonly cited reason for using supplements is for overall health and wellness and to fill nutrient gaps in the diet. Cardiovascular disease and cancer are the 2 leading causes of death and combined account for approximately half of all deaths in the US annually. Inflammation and oxidative stress have been shown to have a role in both cardiovascular disease and cancer, and dietary supplements may have anti-inflammatory and antioxidative effects. <h3>Objective</h3> To update its 2014 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a review of the evidence on the efficacy of supplementation with single nutrients, functionally related nutrient pairs, or multivitamins for reducing the risk of cardiovascular disease, cancer, and mortality in the general adult population, as well as the harms of supplementation. <h3>Population</h3> Community-dwelling, nonpregnant adults. <h3>Evidence Assessment</h3> The USPSTF concludes with moderate certainty that the harms of beta carotene supplementation outweigh the benefits for the prevention of cardiovascular disease or cancer. The USPSTF also concludes with moderate certainty that there is no net benefit of supplementation with vitamin E for the prevention of cardiovascular disease or cancer. The USPSTF concludes that the evidence is insufficient to determine the balance of benefits and harms of supplementation with multivitamins for the prevention of cardiovascular disease or cancer. Evidence is lacking and the balance of benefits and harms cannot be determined. The USPSTF concludes that the evidence is insufficient to determine the balance of benefits and harms of supplementation with single or paired nutrients (other than beta carotene and vitamin E) for the prevention of cardiovascular disease or cancer. Evidence is lacking and the balance of benefits and harms cannot be determined. <h3>Recommendation</h3> The USPSTF recommends against the use of beta carotene or vitamin E supplements for the prevention of cardiovascular disease or cancer. (D recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the use of multivitamin supplements for the prevention of cardiovascular disease or cancer. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the use of single- or paired-nutrient supplements (other than beta carotene and vitamin E) for the prevention of cardiovascular disease or cancer. (I statement)
Filamentous bacteriophage delays healing of Pseudomonas-infected wounds
Authors: Michelle S. Bach, Christiaan R. de Vries, Arya Khosravi, Johanna M. Sweere, Medeea C. Popescu, Qingquan Chen, Sally Demirdjian, Aviv Hargil, Jonas D. Van Belleghem, Gernot Kaber, Maryam Hajfathalian, Elizabeth B. Burgener, Dan Liu, Quynh-Lam Tran, Tejas Dharmaraj, Maria Birukova, Vivekananda Sunkari, Swathi Balaji, Nandini Ghosh, Shomita S. Mathew-Steiner, Mohamed S. El Masry, Sundeep G. Keswani, Niaz Banaei, Laurence Nedelec, Chandan K. Sen, Venita Chandra, Patrick R. Secor, Gina A. Suh, Paul L. Bollyky
Journal: Cell Reports Medicine (2022)

Chronic wounds infected by Pseudomonas aeruginosa (Pa) are characterized by disease progression and increased mortality. We reveal Pf, a bacteriophage produced by Pa that delays healing of chronically infected wounds in human subjects and animal models of disease. Interestingly, impairment of wound closure by Pf is independent of its effects on Pa pathogenesis. Rather, Pf impedes keratinocyte migration, which is essential for wound healing, through direct inhibition of CXCL1 signaling. In support of these findings, a prospective cohort study of 36 human patients with chronic Pa wound infections reveals that wounds infected with Pf-positive strains of Pa are more likely to progress in size compared with wounds infected with Pf-negative strains. Together, these data implicate Pf phage in the delayed wound healing associated with Pa infection through direct manipulation of mammalian cells. These findings suggest Pf may have potential as a biomarker and therapeutic target in chronic wounds.
Strong Association of Combined Genetic Deficiencies in the Classical Complement Pathway With Risk of Systemic Lupus Erythematosus and Primary Sjögren's Syndrome
Authors: Christian Lundtoft, Christopher Sjöwall, Solbritt Rantapää‐Dahlqvist, Anders A. Bengtsson, Andreas Jönsen, Pascal Pucholt, Yee Ling Wu, Emeli Lundström, Maija‐Leena Eloranta, Iva Gunnarsson, Eva Baecklund, Roland Jonsson, Daniel Hammenfors, Helena Forsblad‐d'Elia, Per Eriksson, Thomas Mandl, Sara Bucher, Katrine B. Norheim, Svein Joar Auglaend Johnsen, Roald Omdal, Marika Kvarnström, Marie Wahren‐Herlenius, Lennart Truedsson, Bo Nilsson, Sergey V. Kozyrev, Matteo Bianchi, Kerstin Lindblad‐Toh, Chack‐Yung Yu, Gunnel Nordmark, Johanna K. Sandling, Elisabet Svenungsson, Dag Leonard, Lars Rönnblom
Journal: Arthritis & Rheumatology (2022)

Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjögren's syndrome (SS) has not been studied systematically. This study was undertaken to investigate potential associations of heterozygous C2 deficiency and C4 copy number variation with clinical manifestations in patients with SLE and patients with primary SS.
Contribution of Genome-Wide Polygenic Score to Risk of Coronary Artery Disease in Childhood Cancer Survivors
Authors: Yadav Sapkota, Qi Liu, Nan Li, Neel S. Bhatt, Matthew J. Ehrhardt, Carmen L. Wilson, Zhaoming Wang, John L. Jefferies, Jinghui Zhang, Gregory T. Armstrong, Melissa M. Hudson, Leslie L. Robison, Daniel A. Mulrooney, Yutaka Yasui
Journal: JACC CardioOncology (2022)

Adverse cardiovascular outcomes such as coronary artery disease (CAD) are the leading noncancer causes of morbidity and mortality among childhood cancer survivors.The aim of this study was to assess the role of a genome-wide polygenic score (GPS) for CAD, well validated in the general population, and its interplay with cancer-related risk factors among childhood cancer survivors.In a cohort study of 2,472 5-year childhood cancer survivors from the St. Jude Lifetime Cohort, the association between the GPS and the risk of CAD was performed using Cox regression models adjusted for age at cancer diagnosis, sex, cumulative dose of anthracyclines, and mean heart radiation dose.Among survivors of European ancestry, the GPS was significantly associated with the risk of CAD (HR per 1 SD of the GPS: 1.25; 95% CI: 1.04-1.49; P = 0.014). Compared with the first tertile, survivors in the upper tertile had a greater risk of CAD (1.51-fold higher HR of CAD [95% CI: 0.96-2.37; P = 0.074]), although the difference was not statistically significant. The GPS-CAD association was stronger among survivors diagnosed with cancer at age <10 years exposed to >25 Gy heart radiation (HR top vs. bottom tertile of GPS: 15.49; 95% CI: 5.24-45.52; Ptrend = 0.005) but not among those diagnosed at age ≥10 years (Ptrend ≥ 0.77) and not among those diagnosed at age <10 years exposed to ≤25 Gy heart radiation (Ptrend = 0.23). Among high-risk survivors, defined by an estimated relative hazard ≥3.0 from fitted Cox models including clinical risk factors alone, the cumulative incidence of CAD at 40 years from diagnosis was 29% (95% CI: 13%-45%). After incorporating the GPS into the model, the cumulative incidence increased to 48% (95% CI: 26%-69%).Childhood cancer survivors are at risk for premature CAD. A GPS may help identify those who may benefit from targeted screening and personalized preventive interventions.
Hypoxia-inducible lentiviral gene expression in engineered human macrophages
Authors: Harrison K Chinn, Jennifer L Gardell, Lisa R Matsumoto, Kevin P Labadie, Tara N Mihailovic, Nicole A P Lieberman, Amira Davis, Venu G Pillarisetty, Courtney A Crane
Journal: Journal for ImmunoTherapy of Cancer (2022)

Human immune cells, including monocyte-derived macrophages, can be engineered to deliver proinflammatory cytokines, bispecific antibodies, and chimeric antigen receptors to support immune responses in different disease settings. When gene expression is regulated by constitutively active promoters, lentiviral payload gene expression is unregulated, and can result in potentially toxic quantities of proteins. Regulated delivery of lentivirally encoded proteins may allow localized or conditional therapeutic protein expression to support safe delivery of adoptively transferred, genetically modified cells with reduced capacity for systemic toxicities. In this study, we engineered human macrophages to express genes regulated by hypoxia responsive elements included in the lentiviral promoter region to drive conditional lentiviral gene expression only under hypoxic conditions. We tested transduced macrophages cultured in hypoxic conditions for the transient induced expression of reporter genes and the secreted cytokine, interleukin-12. Expression of hypoxia-regulated genes was investigated both transcriptionally and translationally, and in the presence of human tumor cells in a slice culture system. Finally, hypoxia-regulated gene expression was evaluated in a subcutaneous humanized-mouse cancer model. Engineered macrophages were shown to conditionally and tranisently express lentivirally encoded gene protein products, including IL-12 in hypoxic conditions in vitro. On return to normoxic conditions, lentiviral payload expression returned to basal levels. Reporter genes under the control of hypoxia response elements were upregulated under hypoxic conditions in the presence of human colorectal carcinoma cells and in the hypoxic xenograft model of glioblastoma, suggesting utility for systemic engineered cell delivery capable of localized gene delivery in cancer. Macrophages engineered to express hypoxia-regulated payloads have the potential to be administered systemically and conditionally express proteins in tissues with hypoxic conditions. In contrast to immune cells that function or survive poorly in hypoxic conditions, macrophages maintain a proinflammatory phenotype that may support continued gene and protein expression when regulated by conditional hypoxia responsive elements and naturally traffic to hypoxic microenvironments, making them ideal vehicles for therapeutic payloads to hypoxic tissues, such as solid tumors. With the ability to fine-tune delivery of potent proteins in response to endogenous microenvironments, macrophage-based cellular therapies may therefore be designed for different disease settings.
Big data and long COVID
Authors: None The Lancet Digital Health
Journal: The Lancet Digital Health (2022)

In this issue, Emily Pfaff and colleagues show that machine learning analysis of electronic health records could be crucial in diagnosing patients with long COVID. This is the latest in a plethora of studies to use big data to determine prevalence, symptoms, or risk factors for long COVID. But is big data helping to treat patients with this heterogeneous condition, or should we be redirecting our efforts elsewhere?
Antibody-based redirection of universal Fabrack-CAR T cells selectively kill antigen bearing tumor cells
Authors: Yi-Chiu Kuo, Cheng-Fu Kuo, Kurt Jenkins, Alfur Fu-Hsin Hung, Wen-Chung Chang, Miso Park, Brenda Aguilar, Renate Starr, Jonathan Hibbard, Christine Brown, John C Williams
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Chimeric antigen receptor (CAR) T cells engineered to recognize and target tumor associated antigens have made a profound impact on the quality of life for many patients with cancer. However, tumor heterogeneity and intratumoral immune suppression reduce the efficacy of this approach, allowing for tumor cells devoid of the target antigen to seed disease recurrence. Here, we address the complexity of tumor heterogeneity by developing a universal CAR. Method We constructed a universal Fabrack-CAR with an extracellular domain composed of the non-tumor targeted, cyclic, twelve residue meditope peptide that binds specifically to an engineered binding pocket within the Fab arm of monoclonal antibodies (mAbs). As this site is readily grafted onto therapeutic mAbs, the antigen specificity of these universal Fabrack-CAR T cells is simply conferred by administering mAbs with specificity to the heterogeneous tumor. Results Using in vitro and in vivo studies with multiple meditope-engineered mAbs, we show the feasibility, specificity, and robustness of this approach. These studies demonstrate antigen- and antibody-specific T cell activation, proliferation, and IFNγ production, selective killing of target cells in a mixed population, and tumor regression in animal models. Conclusion Collectively, these findings support the feasibility of this universal Fabrack-CAR T cell approach and provide the rationale for future clinical use in cancer immunotherapy.
The Effects of Coexposure to Extremes of Heat and Particulate Air Pollution on Mortality in California: Implications for Climate Change
Authors: Md Mostafijur Rahman, Rob McConnell, Hannah Schlaerth, Joseph Ko, Sam Silva, Frederick W. Lurmann, Lawrence Palinkas, Jill Johnston, Michael Hurlburt, Hao Yin, George Ban-Weiss, Erika Garcia
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Extremes of heat and particulate air pollution threaten human health and are becoming more frequent because of climate change. Understanding the health impacts of coexposure to extreme heat and air pollution is urgent. Objectives: To estimate the association of acute coexposure to extreme heat and ambient fine particulate matter (PM2.5) with all-cause, cardiovascular, and respiratory mortality in California from 2014 to 2019. Methods: We used a case-crossover study design with time-stratified matching using conditional logistic regression to estimate mortality associations with acute coexposures to extreme heat and PM2.5. For each case day (date of death) and its control days, daily average PM2.5 and maximum and minimum temperatures were assigned (0- to 3-day lag) on the basis of the decedent’s residence census tract. Measurements and Main Results: All-cause mortality risk increased 6.1% (95% confidence interval [CI], 4.1–8.1) on extreme maximum temperature-only days and 5.0% (95% CI, 3.0–8.0) on extreme PM2.5-only days, compared with nonextreme days. Risk increased by 21.0% (95% CI, 6.6–37.3) on days with exposure to both extreme maximum temperature and PM2.5. Increased risk of cardiovascular and respiratory mortality on extreme coexposure days was 29.9% (95% CI, 3.3–63.3) and 38.0% (95% CI, −12.5 to 117.7), respectively, and were more than the sum of individual effects of extreme temperature and PM2.5 only. A similar pattern was observed for coexposure to extreme PM2.5 and minimum temperature. Effect estimates were larger over age 75 years. Conclusions: Short-term exposure to extreme heat and air pollution alone were individually associated with increased risk of mortality, but their coexposure had larger effects beyond the sum of their individual effects.